1. Field of the Invention
The present invention relates to methods and systems for the delivery of drugs to patients in need thereof.
2. Description of the Prior Art
Providing and maintaining adequate concentrations of bioactive agents, such as drugs, for example, in the pre-corneal tear film for extended periods of time is one of the major problems plaguing methods and systems for ocular drug delivery. When they are applied as eye drops, most drugs penetrate poorly through the cornea. Drainage of instilled drug with the tear fluid, and absorption through the conjunctiva leads to a short duration of action. The additional pre-corneal factors that contribute to the poor ocular bio-availability of many drugs when instilled in the eye as drops are tear turnover and drug binding to tear fluid proteins. In addition to the above factors, the rate of corneal uptake is high at early times, but it declines rapidly. This may lead to a transient period of overdose and associated risk of side effects followed by an extended period of sub-therapeutic levels before the administration of next dose. All the above factors indicate the need for an ocular drug delivery system that will be as convenient as a drop but will serve as a controlled release vehicle [Nagarsenker, M. S., Londhe, V. Y., Nadkarni, G. D., “Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery”, Int. J. of Pharm., 1990, 190: 63-71].
Topical delivery via eye drops that accounts for about 90% of all ophthalmic formulations is very inefficient and in some instances leads to serious side effects [Lang, J. C., “Ocular drug delivery conventional ocular formulations”. Adv. Drug Delivery, 1995, 16: 39-43]. Only about 5% of the drug applied as drops penetrate through the cornea and reaches the ocular tissue, while the rest is lost due to tear drainage. [Bourlais, C. L., Acar, L., Zia H., Sado, P. A., Needham, T., Leverge, R., “Ophthalmic drug delivery systems”, Progress in retinal and eye research, 1998, 17, 1: 33-58]. The drug mixes with the fluid present in the tear film upon instillation and has a short residence time of about 2-5 minutes in the film. About 5% of the drug gets absorbed and the remaining flows through the upper and the lower canaliculi into the lacrimal sac. The drug containing tear fluid is carried from the lacrimal sac into the nasolacrimal duct, and eventually, the drug gets absorbed into the bloodstream. This absorption leads to drug wastage and more importantly, the presence of certain drugs in the bloodstream may lead to undesirable side effects. For example, beta-blockers such as Timolol that is used in the treatment of wide-angle glaucoma may have a deleterious effect on heart [TIMPOTIC® prescribing information, supplied by MERCK]. Furthermore, application of ophthalmic drugs as drops may result in a rapid variation in drug delivery rates to the cornea that limits the efficacy of therapeutic systems [Segal, M., “Patches, pumps and timed release”, FDA Consumer magazine, October 1991]. Thus, there is a need for new ophthalmic drug delivery systems that increase the residence time of the drug in the eye, thereby reducing wastage and minimizing or eliminating side effects.
There have been a number of attempts in the past to use contact lenses for ophthalmic drug delivery; however, all of these focused on soaking the lens in drug solution followed by insertion into the eye. In one of the studies, the authors focused on soaking the lens in eye-drop solutions for one hour followed by lens insertion in the eye [Hehl, E. M., Beck, R., Luthard K., Guthoff R., “Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses”, European Journal of Clinical Pharmacology, 1999, 55 (4): 317-323]. Five different drugs were studied and it was concluded that the amount of drug released by the lenses are lower or of the same order of magnitude as the drug released by eye drops. This happened perhaps because the maximum drug concentration obtained in the lens matrix is limited to the equilibrium concentration. In another study researchers developed a contact lens with a hollow cavity by bonding together two separate pieces of lens material [Nakada, K., Sugiyama, A., “Process for producing controlled drug-release contact lens, and controlled drug-release contact lens thereby produced”; U.S. Pat. No. 6,027,745, May 29, 1998]. The compound lens is soaked in the drug solution. The lens imbibes the drug solution and slowly releases it upon insertion in the eye. The compound lens suffers from the same limitations as the drug-soaked lens because the concentration of the drug in the cavity is the same as the concentration of the drug in the drops and thus such a lens can supply the drug for a limited amount of time.
Furthermore, the presence of two separate sheets of lens material leads to smaller oxygen and carbon dioxide permeabilities that can cause an edema in the corneal tissue. The other studies and patents listed below suffer from the same limitations because they are also based on soaking of contact lenses or similar devices in drug-solutions followed by insertion into the eye [Hillman, J. S., “Management of acute glaucoma with Pilocarpine-soaked hydrophilic lens” Brit. J. Ophthal. 58 (1974) p. 674-679, Ramer, R. and Gasset, A., “Ocular Penetration of Pilocarpine:” Ann. Opthalmol. 6, (1974) p. 1325-1327, Montague, R. and Wakins, R., “Pilocarpine dispensation for the soft hydrophilic contact lens” Brit. J. Ophthal. 59, (1975) p. 455-458, Hillman, J., Masters, J. and Broad, A. “Pilocarpine delivery by hydrophilic lens in the management of acute glaucoma” Trans. Ophthal. Soc. U. K. (1975) p. 79-84, Giambattista, B., Virno, M., Pecori-Giraldi, Pellegrino, N. and Motolese, E. “Possibility of Isoproterenol Therapy with Soft Contact Lenses: Ocular Hypotension Without Systemic Effects” Ann. Opthalmol 8 (1976) p. 819-829, Marmion, V. J. and Yardakul, S. “Pilocarpine administration by contact lens” Trans. Ophthal. Soc. U. K. 97, (1977) p. 162-3, U.S. Pat. No. 6,410,045, Drug delivery system for antiglaucomatous medication, Schultz; Clyde Lewis, Mint; Janet M; U.S. Pat. No. 4,484,922, Occular device, Rosenwald; Peter L., U.S. Pat. No. 5,723,131, Contact lens containing a leachable absorbed material, Schultz; Clyde L. Nunez; Ivan M.; Silor; David L.; Neil; Michele L.].
A number of researchers have trapped proteins, cells and drugs in hydrogel matrices by polymerizing the monomers that comprise the hydrogel, in presence of the encapsulated species [Elisseeff, J., McIntosh, W., Anseth, K., Riley, S., Ragan, P., Langer, R., “Photoencapsulation of chondrocytes in poly(ethylene oxide)-based semi-interpenetrating networks”, Journal of Biomedical Materials Research, 2000, 51 (2): 164-171; Ward, J. H., Peppas, N. A., “Preparation of controlled release systems by free-radical UV polymerizations in the presence of a drug”, Journal of Controlled Release, 2001, 71 (2): 183-192; Scott, R. A., Peppas, N. A., “Highly crosslinked, PEG-containing copolymers for sustained solute delivery”, Biomaterials, 1999, 20 (15): 1371-1380; Podual, K., Doyle F. J., Peppas N. A., “Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase”, Polymer, 2000, 41 (11): 3975-3983; Colombo, P., Bettini, R., Peppas, N. A., “Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug”, Journal of Controlled Release, 1999, 61 (1,2): 83-91; Ende, M. T. A., Peppas, N. A., “Transport of ionizable drags and proteins in crosslinked poly(acrylic acid) and poly(acrylic acid-co-2-hydroxyethyl methacrylate) hydrogels. 2. Diffusion and release studies”, Journal of Controlled Release, 1997, 48 (1): 47-56; U.S. Pat. No. 4,668,506]. Direct entrapment of drug could increase loading but it does not increase the duration of release.
A number of researchers have focused on developing ‘imprinted’ contact lenses [Hiratani H, Alvarez-Lorenzo C—“The nature of backbone monomers determines the performance of imprinted soft contact lenses as timolol drug delivery systems” Biomaterials 25, 1105-1113, 2004; Hiratani H, Fujiwara A, Tamiya Y, Mizutani Y, Alvarez-Lorenzo C—“Ocular release of timolol from molecularly imprinted soft contact lenses” Biomaterials 26, 1293-1298, 2005; Hiratani H, Mizutani Y, Alvarez-Lorenzo C-“Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities” Macromol Biosci 5,728-733, 2005: Alverez-Lorenzo C, Hiratani H, Gomez-Amoza J L, Martinez-Pacheco R, Souto C, Concheiro A—“Soft contact lenses capable of sustained delivery of timolol” J Pharm Sci 91, 2182-2192, 2002; Hiratani H, Alvarez-Lorenzo C—“Timolol uptake and release by imprinted soft contact lenses made of N,N-diethylacrylamide and methacrylic acid” J Control Release 83,223-230, 2002]. These articles disclose that imprinting leads to an increase in the partition coefficients and slower release of drugs, but the increase is not very substantial, and these lenses typically have an initial burst release.
To substantially increase the duration of drug release, Chauhan et al suggested dispersing in contact lenses nanoparticles of ophthalmic bioactive agents nanoencapsulated in a material from which the ophthalmic drug is capable of diffusion into and migration through the contact lens and into the post-lens tear film when the contact lens is placed on the eye. The particle size of the nanoparticles and the number thereof dispersed in the contact lens are such that the contact lens remains substantially transparent. [United States Published Patent Applications 20040241207 and 20040096477], Chauhan, Anuj; http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=2&f=G&1=50&col=AND&d=PG01&s1=gulsen&s2=chauhan&OS=gulsen+AND+chauhan&RS=gulsen+AND+chauhan-h2http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=2&f=G&1=50&col=AND&d=PG01&s1=gulsen&s2=chauhan&OS=gulsen+AND+chauhan&RS=gulsen+AND+chauhan-h4Gulsen, Derya, “Ophthalmic drug delivery system”, Gulsen D, Chauhan A—“Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle”. Int J Pharm 292, 95-117, 2005., Gulsen D, Chauhan A—“Ophthalmic drug delivery through contact lenses”. Invest Ophth Vis Sci 45, 2342-2347, 2004]. Also Graziacascone et al. discloses a study on encapsulating lipophilic drugs inside nanoparticles, and entrapping the particles in hydrogels. [Graziacascone, M., Zhu, Z., Borselli, F., Lazzeri, L., “Poly(vinyl alcohol) hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA nanoparticles”, Journal of Material Science: Materials in Medicine, 2002, 13: 29-32]. They used PVA hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA particles. There are two main advantages of entrapment of drug in nanoparticles over soaking and direct entrapment of drug in a gel. First, if the solute is directly trapped in the gel, the release rates are controlled by diffusion through the gel. Contact lenses must be very thin (about 100 μm thick) and only lightly crosslinked to ensure high oxygen permeability. Thus, if drugs are directly trapped in the lens during polymerization, they will be released in a short period of time. If the drugs are trapped inside the nanoparticles, and if the nanoparticles are designed to release drugs slowly, then a contact lens loaded with the drug containing particles can release drug for longer periods of time. Secondly, since the solubility of the hydrophobic drugs is much higher in oil, a significantly higher drug loading can be achieved by entrapping the drug in oil filled nanoparticles or nanocapsules, and subsequently, dispersing these particles in a hydrogel matrix.
In a copending patent application there is disclosed a bioactive agent delivery system comprising a substantially optically transparent contact lens having dispersed therein (1) an ophthalmically bioactive agent, the agent being capable of diffusion through the contact lens and into the post-lens tear film when the contact lens is placed on the eye and (2) associated with the bioactive agent, at least one ophthalmically compatible surfactant, the polymeric surfactant being present in an amount sufficient to attenuate the rate of migration of the bioactive agent through the contact lens.
It is an object of the present invention to provide a novel bioactive agent delivery system, particularly adapted for delivering the agent to the eye.